Amine oxidases as important agents of pathological processes of rhabdomyolysis in rats.

In this study we have tested an idea on the important role of amine oxidases (semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase) as an additional source of oxidative/carbonyl stress under glycerol-induced rhabdomyolysis, since the enhanced formation of reactive oxygen species and reactive carbonyl species in a variety of tissues is linked to various diseases. In our experiments we used the sensitive fluorescent method devised for estimation of amine oxidases activity in the rat kidney and thymus as targeted organs under rhabdomyolysis. We have found in vivo the multiple rises in activity of semicarbazide-sensitive amine oxidase, diamine oxidase, polyamine oxidase (2-4.5 times) in the corresponding cell fractions, whole cells or their lysates at the 3-6th day after glycerol injection. Aberrant antioxidant activities depended on rhabdomyolysis stage and had organ specificity. Additional treatment of animals with metal chelator 'Unithiol' adjusted only the activity of antioxidant enzymes but not amine oxidases in both organs. Furthermore the in vitro experiment showed that Fenton reaction (hydrogen peroxide in the presence of iron) products alone had no effect on semicarbazide-sensitive amine oxidase activity in rat liver cell fraction whereas supplementation with methylglyoxal resulted in its significant 2.5-fold enhancement. Combined action of the both agents had additive effect on semicarbazide-sensitive amine oxidase activity. We can assume that biogenic amine and polyamine catabolism by amine oxidases is upregulated by oxidative and carbonyl stress factors directly under rhabdomyolysis progression, and the increase in catabolic products concentration contributes to tissue damage in glycerol-induced acute renal failure and apoptosis stimulation in thymus.

Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency.

Exercise induced rhabdomyolysis is a complication of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (TFP) deficiency that frequently leads to exercise avoidance. Dietary therapy for most subjects includes medium-chain triglyceride (MCT) supplementation but analysis of diet records indicates that the majority of patients consume oral MCT only with breakfast and at bedtime. We hypothesized that MCT immediately prior to exercise would provide an alternative fuel source during that bout of exercise and improve exercise tolerance in children with LCHAD deficiency. Nine subjects completed two 45 min moderate intensity (60-70% predicted maximum heart rate (HR)) treadmill exercise tests. Subjects were given 4 oz of orange juice alone or orange juice and 0.5 g MCT per kg lean body mass, 20 min prior to exercise in a randomized cross-over design. ECG and respiratory gas exchange including respiratory quotient (RQ) were monitored. Blood levels of acylcarnitines, creatine kinase, lactate, and beta-hydroxybutyrate were measured prior to and immediately after exercise, and again following 20 min rest. Creatine kinase and lactate levels did not change with exercise. There was no significant difference in RQ between the two exercise tests but there was a decrease in steady-state HR following MCT supplementation. Cumulative long-chain 3-hydroxyacylcarnitines were 30% lower and beta-hydroxybutyrate was three-fold higher after the MCT-pretreated exercise test compared to the test with orange juice alone. Coordinating MCT supplementation with periods of increased activity may improve the metabolic control of children with LCHAD and TFP deficiency following exercise.

HMG-CoA reductase inhibitors and coenzyme Q10.

The most concerning adverse reaction with HMG-CoA reductase inhibitors (statins) is myotoxicity. Statins inhibit the production of mevalonate, a precursor of both cholesterol and coenzyme Q10, a compound believed to be crucial for mitochondrial function and the provision of energy for cellular processes. There is speculation that a reduction in coenzyme Q10 concentrations may promote the myopathies that have been associated with statin treatment as a result of mitochondrial damage. Although studies have repeatedly demonstrated a reduction in circulating coenzyme Q10 concentrations with statin therapy, it is unclear as to whether tissue levels of coenzyme Q10 are significantly affected. Coenzyme Q10 supplementation has been shown to reverse statin-induced decreases in circulating coenzyme Q10 concentrations, although the effect of supplementation on tissue coenzyme Q10 concentrations and any resulting clinical benefit has not been adequately assessed. Although there is not much of a safety concern with coenzyme Q10 supplementation, there is also not enough evidence to support its routine use for preventing the adverse effects of statin therapy, and it is therefore not recommended for this purpose at this time.

Potential role of carnitine in patients with renal insufficiency.

Carnitine metabolism is altered in renal insufficiency and influenced by the treatment modalities. Chronically uremic patients with end-stage renal disease under conservative therapy, hemodialysis, or peritoneal dialysis show low, normal, or elevated serum levels of TC and a distorted pattern of FC, SCAC, and LCAC. HD induces a marked depletion of FC, while predialytic elevated SCAC and LCAC are in the normal range at the end of dialysis treatment. All carnitine fractions rapidly return to predialysis levels 6 h after HD due to a transport of carnitine from muscle stores to plasma pool. Muscle carnitine content is elevated in chronic uremic patients under conservative therapy. Normal or decreased levels are observed in patients on long-term HD treatment. In addition, weekly losses of carnitine in patients undergoing HD or peritoneal dialysis do not exceed urinary carnitine excretion of CO. Supplementation with currently recommended doses (1-2 g L-carnitine i.v. at the end of each HD) is followed by a marked rise in plasma carnitine levels, suggesting limited carnitine utilization in uremia. Therefore, lower carnitine doses and modified application regimens should be considered to avoid exaggerated plasma levels of carnitine and carnitine esters. Furthermore, carnitine application has been reported to show beneficial, worsening, or no effect on the deranged lipid metabolism of the uremic patients. In patients undergoing CAPD or IPD predominantly normal serum carnitine levels have been reported. On the other hand, SCAC and LCAC esters are markedly elevated in these patients. After kidney transplantation the pattern of carnitine fractions is fully normalized in patients with plasma creatinine less than or equal to 120 mumol/l.(ABSTRACT TRUNCATED AT 250 WORDS)